Journeys to Failure that Litter the Path to Developing New Cancer Therapeutics
Authors: Tito Fojo
Journal: JAMA Network Open (2023)

describe a cross-sectional study undertaken to understand the reasons for failure and associated clinical expenses underlying the unsuccessful development of 16 inhibitors of insulinlike growth factor-1 receptor (IGF-1R) assessed in 183 clinical trials, in which IGF-1R inhibitors were administered to more than 12 000 patients with a diagnosis of cancer, at an estimated cost of more than $1.6 billion.Their contribution highlights a problem in the development of cancer therapeutics with broad ramifications.Although the algorithm used in the study to estimate drug development costs has limitations, 1 a difference of a few hundred million dollars is, unfortunately, irrelevant in this context.The real issues are why did this happen, what can we do to avoid it in the future, and what are its ethical consequences?This imbroglio epitomizes a problem that has always existed, which accelerated when large pharmaceutical companies ceded the discovery of new agents to smaller biotechnology companies, a decision with predictable consequences for which we now pay the price.These journeys to failure often begin with experiments that are, unfortunately, often not reproducible but nevertheless generate widespread interest. 2Next, at a dozen or more biotechnology companies, individuals with access to the same data and overlapping experiences all come to similar conclusions and begin developing therapeutics for the target.Development proceeds more rapidly in some cases and slower in others.The fastest-developed, novel therapeutics reach patients first, and in early studies, they underperform, but hope springs eternal and emphasis shifts to soft end points, especially clinical benefit.Large pharmaceutical companies, which are anxious to be first to market, take some of the novel therapeutics and develop them aggressively.Soon reports begin to emerge that the novel therapeutics are not working as well as hoped, which should be an important sign to discontinue further development, but by now hundreds of millions of dollars have been invested in development of a dozen or more "me-too therapeutics," 3 and with success only a few hundred million dollars away, stopping is no longer an option.Each biotechnology or pharmaceutical company thinks the next agent is better than the competitor's, but they all leveraged similar data and experiences, and, with rare exceptions, none will succeed.Failures quickly accumulate, and as latecomers turn to other cancers with different histologic profiles with even less support for success, failures accumulate even more rapidly.Years into development, with billions of dollars spent in vain, reality begins to set in and development slows, such as that for mitotic inhibitors 4 and, soon, many modulators of checkpoint inhibitors.Everyone moves on.Most individuals involved in these journeys to failure leave their company to go to another, and no lessons are learned.Then the journeys begin anew with the next promising target.Everywhere in the other journeys to failure and in the unsuccessful development of IGF-1R inhibitors, warning signs seen in the context of approved drugs were ignored.First among the signs ignored is the strength of the supporting data.Although good preclinical data are very valuable, unfortunately, as Jentzsch and colleagues 1 note, bad or highly biased data are abundant.Additional signs ignored are those of precursors that have already failed, a recurring theme in these journeys where those developing me-too candidates discount the failures of competitors and continue development.Given that for practically all targets for which drugs were successfully developed, not one, but several therapeutics have been developed and approved (eg, CDK4/6 inhibitors, checkpoint inhibitors, PARP inhibitors, EGFR tyrosine kinase inhibitors [TKIs], NTRK inhibitors, and countless others), all by skilled individuals with access to the same data, the likelihood that an active therapeutic will be found after the first dozen therapeutics have failed is very low.